To develop an oral anti-TNF antibody therapeutic that is safe and effective enough to be used as a first line therapy for inflammatory bowel disease. Problem: Inflammatory bowel disease (IBD) comprises two chronic inflammatory disorders of the gastrointestinal tract: Crohn's disease and ulcerative colitis. Approximately 1 million people in the U.S. suffer from IBD, with direct healthcare costs of $6.3B/year and costs for lost work of $3.6B/year. Injectable anti-TNF antibodies are highly effective in treating inflammatory bowel disease. However, because they neutralize TNF throughout the body, their use is associated with serious side effects such as reactivation of tuberculosis and long-term risk of malignancy. This limits their use to 2nd or 3rd line treatment of severe/refractory IBD. Avaxia's Solution: Avaxia is developing AVX-470h, an oral polyclonal anti-TNF antibody therapeutic for IBD from the early milk (colostrum) of immunized cows. Bovine colostral antibodies are ideal for oral delivery, as the antibodies are stable to gastric digestion and there is a long history of safe human exposure. With the support of the SBIR Phase I grant, we established that oral delivery of AVX-470m (bovine antibody specific for murine TNF) significantly reduced the severity of colitis in the well-established TNBS and DSS mouse models of IBD while blood levels remained low. We hypothesize that oral administration of AVX-470h (bovine antibody specific for human TNF) to human subjects will enable targeted distribution to the site of inflammation in the gut, with minimal systemic exposure, thus eliminating side effects while maintaining therapeutic efficacy. Specific Aims: 1) To define the pharmacokinetics and determinants of efficacy in animal models of IBD. AVX- 470m will be evaluated in murine TNBS- and DSS-induced colitis models, selecting a single model for further analysis and defining the effects of dose and dosing regimen on efficacy, local and systemic exposure, immune function and immunogenicity. These studies will define the variables important in the clinical use and testing of AVX-470h. 2) To produce AVX-470h (bovine anti-human TNF antibody) for use in preclinical development in Aim 3. Cows will be immunized with human TNF and immunoglobulin will be purified from the immune colostrum. 3) To define the pharmacology of TNF inhibition by AVX-470m and AVX-470h. The molecular and cellular pharmacology of AVX-470m and AVX-470h will be defined by measuring TNF binding, neutralization and specificity. The goal of Aim 3 is to bridge between the anti-murine TNF (AVX-470m) used in preclinical studies and the anti-human TNF (AVX-470h) to be used in clinical trials. Development of clinical drug supply, toxicology work and regulatory filings for AVX-470h will be carried out in parallel with SBIR Phase II studies but funded independently. If AVX-470m is efficacious in murine colitis models with minimal systemic exposure and the TNF pharmacology profile of AVX-470h mimics AVX-470m, we will file an IND and proceed to clinical testing of AVX-470h. PUBLIC HEALTH RELEVANCE: Crohn's Disease and Ulcerative Colitis, collectively known as inflammatory bowel disease (IBD), are serious chronic diseases that afflict over 1 million Americans, costing the U.S. economy an estimated $6.3 billion in direct healthcare costs and $3.6 billion in lost work time each year. Our SBIR Phase I studies showed that AVX-470, Avaxia's orally delivered anti-TNF antibody therapeutic, is effective at treating mouse models of IBD and does not produce blood levels of antibody that are associated with immunosuppression (a major side effect of currently marketed anti-TNF antibodies administered by injection that limits their use to patients with severe disease). This proposal is focused on advancing AVX-470 toward an IND filing with the goal of developing an oral anti-TNF antibody therapeutic that is safe and effective enough to be used as a first line therapy to prevent the progression of IBD to severe disease.